126: Smith-Magenis Syndrome: Chromatin Rewiring to Hyperexcitable Neurons

Lee Y et al., The American Journal of Human Genetics - This episode reviews a study using hiPSC-derived 2D cortical neurons and 3D cortical organoids from individuals with del(17)p11.2 (Smith-Magenis syndrome) to map chromatin, transcriptional, developmental, and electrophysiological consequences of the deletion. Key terms: Smith-Magenis syndrome, del(17)p11.2, hiPSC organoids, chromatin topology, neuronal hyperexcitability. Study Highlights:The authors show that del(17)p11.2 induces local TAD fusion on chromosome 17 and genome-wide chromatin miswiring in hiPSCs and cortical organoids, with widespread transcriptional dysregulation. SMS organoids display reduced growth, enlarged PAX6+ ventricles, impaired progenitor cell-cycle progression, and accelerated neuronal maturation. In 2D cortical neurons, SMS cells exhibit early accelerated dendritic growth, increased excitatory synapse density, and intrinsic hyperexcitability linked to reduced voltage-gated potassium conductance. Together, the models recapitulate neuroanatomical and neurophysiological features of SMS and identify candidate molecular and cellular mechanisms. Conclusion:del(17)p11.2 disrupts 3D chromatin architecture and transcriptional programs, impairing progenitor proliferation and promoting neuronal hyperexcitability, which hiPSC-derived 2D and 3D models faithfully recapitulate and that point to potassium-channel and cell-cycle pathways as potential intervention targets. Music:Enjoy the music based on this article at the end of the episode. Article title:Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models First author:Lee Y Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2025.07.020 Reference:Lee Y.-J., Chang Y.-T., Cho Y., Kowalczyk M., Dragoiescu A., Pacis A., Kailasam S., Lefebvre F., Zhang Q., Gao X., Huang W.-H. (2025). Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models. The American Journal of Human Genetics 112, 1–25. https://doi.org/10.1016/j.ajhg.2025.07.020 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/molecular-and-developmental-deficits-in-smith-magenis-syndrome-human-stem-cell-derived-cortical-neural-models QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-03. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections covering human iPSC-based SMS models (2D neurons and 3D organoids), 3D genome topology (Hi-C/TAD fusion), transcriptional changes (snRNA-seq/bulk RNA-seq), organoid growth and ventriculomegaly, NPC proliferation/cell-cycle defects, 2D neuron maturation and hyperexcitability with potassium-ch- transcript topics: Human iPSC-derived SMS models (2D cortical neurons and 3D cortical organoids); 3D genome architecture and chromatin topology changes (Hi-C, TAD fusion, trans effects); Global transcriptional dysregulation across multiple cortical cell types (snRNA-seq and bulk RNA-seq); Organoid growth impairment and ventriculomegaly-like phenotypes with NPC proliferation defects; NPC cell-cycle perturbations and G1 arrest signatures; Neuron maturation and dendritic expansion with ear...